Loss of heterozygosity is related to p53 mutations and smoking in lung cancer

Abstract

Summary Carcinogenesis results from an accumulation of several genetic alterations. Mutations in the p53 gene are frequent and occur at an early stage of lung carcinogenesis. Loss of multiple chromosomal regions is another genetic alteration frequently found in lung tumours. We have examined the association between p53 mutations, loss of heterozygosity (LOH) at frequently deleted loci in lung cancer, and tobacco exposure in 165 tumours from non-small cell lung cancer (NSCLC) patients. A highly significant association between p53 mutations and deletions on 3p, 5q, 9p, 11p and 17p was found. There was also a significant correlation between deletions at these loci. 86% of the tumours with concordant deletion in the 4 most involved loci (3p21, 5q11-13, 9p21 and 17p13) had p53 mutations as compared to only 8% of the tumours without deletions at the corresponding loci (P < 0.0001). Data were also examined in relation to smoking status of the patients and histology of the tumours. The frequency of deletions was significantly higher among smokers as compared to non-smokers. This difference was significant for the 3p21.3 (hMLH1 locus), 3p14.2 (FHIT locus), 5q11-13 (hMSH3 locus) and 9p21 (D9S157 locus). Tumours with deletions at the hMLH1 locus had higher levels of hydrophobic DNA adducts. Deletions were more common in squamous cell carcinomas than in adenocarcinomas. Covariate analysis revealed that histological type and p53 mutations were significant and independent parameters for predicting LOH status at several loci. In the pathogenesis of NSCLC exposure to tobacco carcinogens in addition to clonal selection may be the driving force in these alterations.

Frequent allelic deletion at the FHIT locus associated with p53 overexpression in squamous cell carcinoma subtype of Taiwanese non-small-cell lung cancers

“…In addition, purified genomic DNA isolated from microdissected DNAs could potentially reduce the masking effects of nontumourous genomic DNA contaminated in tissue specimens and increased LOH frequency. Previous studies have shown that the loss of 3p14.2 is more common in squamous cell carcinomas than in adenocarcinomas (Tsuchiya et al, 1992;Testa et al, 1994;Zienolddiny et al, 2001). Our data are consistent with this association (Table 1).…”

“…The correlation between LOH at the FHIT gene locus and the patients' survival was different in different studies (Fong et al, 1997;Sozzi et al, 1997Sozzi et al, , 1998Burke et al, 1998;Tomizawa et al, 1998). Loss of heterozygosity at the FHIT gene locus in smokers has occurred more frequently than that in nonsmokers Zienolddiny et al, 2001). It was also reported that lack of Fhit staining correlates with LOH at the FHIT 3p14.2 locus, but not at other loci on 3p (Geradts et al, 2000).…”

Roles of Fhit and p53 in Taiwanese surgically treated non-small-cell lung cancers

“…As in the reports mentioned before (Marchetti et al, 1998;Geradts et al, 2000), Fhit expression was not correlated to the abnormality of p53 in smoking patients. A recent study (Zienolddiny et al, 2001) indicated that LOH at 3p, 5q, 9p, 11p, and 17p regions were interdependent and highly associated with mutated TP53 gene in smokers. The significant association of Fhit and p53 protein expressions with smokers in the present study is perhaps related to the size of this series.…”

“…Alteration of the TP53 gene may be involved in the initiation, development, progression, and invasion of lung cancer (Caamano et al, 1991;Sozzi et al, 1992;Marchetti et al 1993;Fontanini et al, 1994). Even though correlation of p53 protein expression with clinical and biological characteristics of lung cancer has been extensively studied, the results of these studies are quite diverse (Top et al, 1995;Passlick et al, 1995;Dalquen et al, 1996;Lee et al 1999;Garinis et al, 2001;Zienolddiny et al, 2001). The results of this study indicated that p53 expression was closely related to distant metastasis of the overall NSCLCs and the adenocarcinoma subtype; and p53 was especially useful as a prognostic factor in adenocarcinoma.…”

“…The correlation between LOH at the FHIT gene locus and the patients' survival is controversial (Fong et al, 1997;Sozzi et al, 1997a, b;Burke et al, 1998;Tomizawa et al, 1998). LOH at the FHIT gene locus in smokers occurred more frequently than that in nonsmokers (Sozzi et al, 1997a;Zienolddiny et al, 2001). It was also reported that there was no correlation between Fhit protein expression with the histotype, tumour stage, survival (Sozzi et al, 1997a;Geradts et al, 2000) and abnormalities of immunohistochemical expression of p53, Rb, and p16 (Geradts et al, 2000).…”